Compositions including antibiotics and methods for using same

ABSTRACT

Compositions including a quinolone component, such as ofloxacin, having fungistatic activity in the compositions, present in an amount effective as an antibiotic when the composition is placed in a mammalian eye, a NSAID component present in an amount to reduce inflammation or pain when the composition is placed in the eye, and a carrier component in an amount effective to act as a carrier for the quinolone component and NSAID component are provided. Methods of using the present compositions, for example, to resolve microbial infections and/or to reduce inflammation and/or pain in a mammalian eye are included within the scope of the present invention. Methods for treating corneal injuries are also included. In addition, methods for treating ocular infections, for example, corneal infections, are included.

RELATED APPLICATION

[0001] This application is a continuation-in-part of application Ser.No. 09/364,334 filed Jul. 30, 1999, and application Ser. No. 09/365,291,filed Jul. 30, 1999, the disclosure of each of which is herebyincorporated in its entirety herein by reference.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to compositions includingantibiotics and to methods for using such compositions. Moreparticularly, the invention relates to compositions includingantibiotics which have added protection against fungal contamination,which reduce inflammation or pain and/or which are useful in thetreatment of corneal ulcers.

[0003] Various antibiotic components have been used in ocularapplications, for example, to control or manage or prevent ocularinfections and the like. Moreover, antibiotic components, such astobramycin have been suggested for use in combination with othermaterials, such as ophthalmically acceptable non-steroidalanti-inflammatory drugs or NSAIDs. See, for example, Fu et al. U.S. Pat.No. 5,414,011, the disclosure of which is incorporated in its entiretyherein by reference. Quinolones, such as ofloxacin, have been used incompositions for treating ocular infections. These antibioticcompositions include one or more additional components which act aspreservatives, for example, benzalkonium chloride (BAK) ororganomercurials.

[0004] Antibiotic compositions, even with preservatives, have beensusceptible to microbial, for example, fungal, contamination. Inaddition, preservatives tend to cause irritation, allergic reactions,and/or other detrimental side effects when the preserved composition isadministered to a patient.

[0005] Thus, it would be advantageous to provide antibioticcompositions, and methods for using such compositions, which have addedprotection against microbial contamination and/or which includerelatively reduced concentrations of preservatives.

[0006] Corneal injuries, such as corneal ulcers and other cornealconditions which are infected or if left untreated are likely to becomeinfected, are quite painful and sometimes require lengthy periods oftime to heal. It would be advantageous to provide compositions andmethods effective to reduce the pain of these corneal injuries, forexample, while such injuries are healing.

SUMMARY OF THE INVENTION

[0007] New antibiotic compositions, for example, for use in mammalianeyes, preferably human eyes, and methods for using such compositionshave been discovered. By administering present compositions to humans oranimals, for example, to the eyes of humans or animals, desiredtherapeutic effects are provided, such as the prevention, control ormanagement or substantial elimination of ocular microbial infections,reductions in inflammation and/or pain, reductions in pain caused bycorneal injuries and the like.

[0008] The present compositions preferably have added protection againstmicrobial, for example, fungal contamination. This feature providesadded assurance to the user that the present compositions are free ofdetrimental microbial contamination. This feature may allow reducedconcentrations of preservatives to be included in the presentcompositions, thereby advantageously reducing detrimental side effectscaused by such preservatives when the compositions are administered topatients. The present compositions can be easily produced, for example,using conventional techniques and can be conveniently used, for example,employing conventional methods of administration.

[0009] In accordance with one aspect of the invention, the compositionscomprise a quinolone component, a NSAID component and a carriercomponent. The quinolone component is present in an amount effective asa antibiotic when the composition is placed in a mammalian eye. In oneuseful embodiment, the quinolone component in the composition hasfungistatic activity. That is, the quinolone components in the presentcompositions have sufficient anti-fungal properties or activity tosubstantially prevent increases in populations of fungi in suchcompositions. In effect, the present quinolone components act aseffective preservatives against fungal growth or contamination in thepresent compositions. The fungistatic activity of the presently usefulquinolone components in the present compositions provide benefits, forexample, as described elsewhere herein, which are surprising andsubstantial. The NSAID component is present in an amount effective toreduce at least one of inflammation and pain when the composition isplaced in a mammalian eye. The carrier component is present in an amounteffective to act as a carrier for the quinolone component and the NSAIDcomponent in the composition, and preferably is ophthalmicallyacceptable.

[0010] The present compositions preferably include a quinolone componentwhich is halogenated, more preferably fluorinated. Very usefulcompositions and results are obtained when the quinolone component is anofloxacin component.

[0011] Although any NSAID component may be used, the NSAID componentsincluded in the present compositions preferably are carboxylic (—COOH)group-containing NSAID components. More preferably, the NSAID componentis a pyrrolo pyrrole component, still more preferably a ketorolaccomponent.

[0012] The present carrier components may contain one or morepharmaceutically or ophthalmically acceptable ingredients, for example,tonicity adjuster components, buffer components, viscosity components,lubricating components, surfactant components, preservative componentsand the like, conventionally used, for example, in ophthalmicformulations. Preferably, the compositions have pH's in thephysiological range of human beings, for example, in the range of about4 to about 8.5.

[0013] The present compositions may be in any form suitable foreffective administration to the human or animal to be treated.Preferably, the compositions are present in a form selected fromsolutions, suspensions, gels, ointments solids and the like which arevery effective for ocular administration. The carrier component mayconveniently be selected and/or compounded to provide the composition inthe form desired.

[0014] Methods of using these compositions are included in the scope ofthe present invention. Such methods comprise administering to a human oranimal, preferably to a mammalian eye, a therapeutically effectiveamounts of the compositions as described herein. Such methods provideone or more benefits to the human or animal treated in accordance withthe present methods. For example, such benefits include prevention,control or management of microbial infections, and reduction ininflammation and/or pain.

[0015] In another aspect of the present invention, methods for treatingcorneal injuries are provided. As used herein, the term “corneal injury”refers to an injury of the cornea which is infected by harmful and/orunwanted microorganism or which, if left untreated is likely to becomeso infected, for example, before this injury heals. A corneal ulcer isan example of a corneal injury. Such methods comprise administering to amammalian eye having a corneal injury a therapeutically effective amountof a composition comprising a quinolone component in an amount effectiveas an antibiotic in the mammalian eye and a NSAID component in an amounteffective, in combination with the quinolone component, to provide areduction in pain caused by the corneal injury. Such reduction in pain,together with the antibiotic effectiveness of the presently usefulcompositions, reduces the discomfort to the patient resulting from thecorneal injury and facilitates or promotes the healing of the injury.The present useful compositions preferably include a carrier componentin an amount effective to act as a carrier for the quinolone componentand the NSAID component in the presently useful composition.

[0016] In another aspect of the present invention, methods for treatingocular infections, such as corneal infections and the like, areprovided. Such methods comprise administering to a mammalian eye havingan infection caused by one or more microbes or pathogens atherapeutically effective amount of a composition comprising a quinolonecomponent in an amount effective as an antibiotic in the mammalian eyeand an effective amount of a NSAID component. In one embodiment, theNSAID component is present in an amount effective to reduce the timeneeded to eliminate the infection relative to identically administeringa similar composition without the NSAID component. The administeringstep preferably is effective to at least inhibit the offendingmicrobe(s) or pathogen(s) from adhering to a surface of the mammalianeye and/or to inhibit colonization of the offending microbe(s) orpathogen(s) in the mammalian eye.

[0017] In another aspect of the invention is provided a preservedcomposition comprising a quinolone component including substantially noadditional components which are effective as preservatives. Preferablythe quinolone is a fluoronated quinolone, more preferably ofloxacin,including enantiomers thereof. Such self-preserved compositions maycontain additional active components, such as an NSAID, to provideadditional therapeutic benefit. The lack of additional preservatives,such as benzalkonium chloride (BAK), which can cause irritation to theeye makes this aspect of the invention particularly advantageous.

[0018] Any and all features described herein and combinations of suchfeatures are included within the scope of the present invention providedthat the features of any such combination are not mutually inconsistent.

[0019] These and other aspects and advantages of the present inventionare in the following detailed description and Examples and claims.

DETAILED DESCRIPTION

[0020] The present compositions comprise quinolone components, NSAIDcomponents and carrier components.

[0021] Preferably, the present quinolone components exhibit fungistaticproperties in the present compositions. That is, the quinolonecomponents in the present compositions preferably are effective topreserve the present compositions against population growth of fungi,such as C. Albicans and A. niger.

[0022] The fungistatic activity or properties of the present quinolonecomponents provide added protection against microbial, for example,fungal, contamination of the present compositions. Such fungistaticactivity can result in reducing the concentration of added preservativecomponents in the present compositions, thereby reducing the risk ofirritation and/or other uncomfortable side effects caused by thepresence of such added preservatives. Even if the present compositionsare substantially free of added preservative components, it has beenfound that many of the present compositions have sufficient preservativeefficacy to meet or exceed the standards of the United StatesPreservative Efficacy Test (USPET).

[0023] The present compositions include quinolone components. A numberof such quinolone components are known and have been used for many yearsin antibiotic applications. For example, nalidixic acid has beenavailable for the treatment of urinary tract infections. The usefulquinolone components preferably are four-quinolones that contain acarboxylic moiety in the three position of the basic structure shownbelow:

[0024] The present quinolone components preferably are halogenated. Forexample, a chlorinated quinolone component, such as9-chloro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyridol[1,2,3-de][1,4]benzozaxine-6carboxylic acid may be used.

[0025] More preferably, the present quinolone components arefluorinated. Examples of such fluorinated quinolones includenorfloxacin, ciprofloxacin and ofloxacin. Such fluorinated quinolonecomponents are highly effective against a range of bacteria and areuseful in treating various microbial infections in the mammalian eye.Prior ofloxacin-containing compositions including such quinolone usedfor this purpose include additional preservatives, for example, BAK.

[0026] It has been found that the present quinolone components, such asofloxacin, have sufficient fungistatic activity to be useful in thepresent compositions to act as a preservative against fungalcontamination.

[0027] The present compositions include an antibiotically effectiveamount of the quinolone component. Such amounts may vary over arelatively broad range depending, for example, on the specific form ofthe composition being used, the specific quinolone component being used,the specific application for the composition, the frequency of use ofthe composition and the like factors. In many situations, the presentcompositions may include a quinolone component in an amount in a rangeof about 0.03% (w/v) or less to about 3% (w/v) or more. Preferably, thepresent compositions include the quinolone component in an amount in therange of about 0.15% (w/v) to about 0.5% (w/v) or about 1.1% (w/v).

[0028] The quinolone component may be any quinolone derivative which isacceptable or suitable for administration to the eye and has at least aportion, preferably a major portion or at least about 50% of theantibiotic effectiveness of the basic quinolone in the presentcomposition in the mammalian eye. The present quinolone component may beselected from the quinolone itself or quinolone hydrates orophthalmically acceptable salts of such quinolones, for example,including acid addition salts such as hydrochlorides, maleates, pamoatesand the like, and alkali metal salts such as sodium and potassium salts,and mixtures thereof and the like.

[0029] The present compositions include a NSAID component in an amounteffective to reduce inflammation and/or pain when the compositions areadministered to a mammalian eye, for example, to prevent or treatdiseases which are either caused by, associated with or accompanied byinflammatory processes and/or pain, including, among others, glaucoma,cystoid macular edema, uveitis, diabetic retinopathy and conjunctivitis,or any trauma caused by eye surgery or eye injury.

[0030] The NSAID component may or may not include a carboxylic (—COOH)group or moiety, or a carboxylic derived group or moiety. In oneembodiment, the NSAID component inhibits the cyclo-oxygenase enzyme,which has two (2) isoforms, referred to as COX-1 and COX-2. Many of thewell known NSAID components are basiclaly non-selective COX inhibitors.NSAID components which are selective COX-2 inhibitors are also known.Both types of NSAID components, that is both non-selective COXinhibitors and selective COX-2 inhibitors are useful in accordance withthe present invention. The NSAID component may be selected fromphenylalkanoic acids, such as diclofenac, flurbiprofen, ketorolac,piroxicam and the like; indoles, such as indomethacin and the like;diarylpyrazoles, such as celecoxib and the like; pyrrolo pyrroles; andother agents that inhibit prostaglandin synthesis. A very useful NSAIDcomponent is the pyrrolo pyrrole which has a propionic acid moiety,known as ketorolac and derivatives thereof, such as non-toxic esters andsalts thereof. Pyrrolo pyrroles have been suggested for use in thetreatment of certain ophthalmic diseases in Waterbury U.S. Pat. No.4,454,151, the disclosure of which is incorporated in its entiretyherein by reference.

[0031] The NSAID component may be present in the present compositions inany suitable concentration effective to reduce inflammation or pain whenthe composition is placed in a mammalian eye. The NSAID componentpreferably is present in an amount in a range of about 0.001% (w/v) orless to about 10% (w/v) or more, and more preferably in a range of about0.02% (w/v) to about 0.5% (w/v) or about 1% (w/v).

[0032] The present carrier components may be selected frompharmaceutically acceptable organic and/or inorganic components which,preferably, in the present compositions are ophthalmically acceptable.As used herein, the term “ophthalmically acceptable” refers to amaterial which, at the concentration or amount in question, iscompatible with ocular tissue, that is the material does not causesignificant or undue detrimental effects when brought into contact withocular tissue. The carrier component preferably is ophthalmicallyacceptable. Preferably, each component of the present compositions isalso compatible with the other components of the compositions.

[0033] Examples of suitable materials useful in the present carriercomponents include water, mixtures of water and water-miscible solventssuch as lower alkanols or aralkanols, vegetable oils, polyalkyleneglycols, petroleum-based jelly, ethyl cellulose, ethyl oleate,carboxymethyl cellulose, polyvinylpyrrolidone, isopropyl mirstate, otherconventionally employed pharmaceutically acceptable materials and thelike.

[0034] The carrier component may also include auxiliary substances suchas emulsifiers, wetting agents, bodying agents, buffer components, acidsand/or bases, tonicity adjuster components, surfactant components,viscosity agents, lubricity components, preservative components, othermaterials useful in ophthalmic formulations and the like, including, butnot limited to, such substances which are conventionally used inophthalmic compositions.

[0035] Examples of optionally useful bodying agents include, but are notlimited to, various polyethylene glycols, carbowaxes, petroleum jellyand the like.

[0036] Suitable buffers include, but are not limited to, inorganicbuffers such as phosphate buffers, borate buffers and the like, andorganic buffers, such as acetate buffers, citrate buffers, tromethamineand the like.

[0037] Tonicity adjusters optionally useful in the present compositionsinclude, but are not limited to, dextrose, potassium chloride and/orsodium chloride and the like, preferably sodium chloride.

[0038] Acids optionally useful in the present compositions include boricacid, hydrochloric acid, acetic acid, other acids which areophthalmically acceptable in the concentrations used, and the like.

[0039] Bases which may be included in the present compositions include,but are not limited to, sodium and/or potassium hydroxides, other alkaliand/or alkaline earth metal hydroxides, organic bases, other bases whichare ophthalmically acceptable in the concentrations used, and the like.

[0040] The acid/bases/buffers preferably are included, if at all, toprovide and/or maintain the present compositions at a pH in thephysiologically acceptable range, more preferably in a range of about 4to about 8.5, still more preferably about 6 to about 8, and especiallyabout 6.8 to about 8.

[0041] Surfactant components optionally useful in the compositions ofthe present invention include, but are not limited to, lipoproteindetergents that when present in the compositions reduce the surfacetension between the compositions and the eye (lacrimal) fluid.Preferably, nonionic surfactants are used.

[0042] Viscosity agents optionally useful in the compositions of thepresent invention include, but are not limited to, cellulose derivativessuch as hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose,hydroxyethyl cellulose, other viscosity inducing materials useful inophthalmic formulations, and the like.

[0043] Lubricating components optionally useful in compositions of thepresent invention include, but are not limited to, polyvinyl alcohol,polyvinylpyrrolidone, carbopol and the like.

[0044] Preservative components optionally useful in the compositions ofthe present invention include, but are not limited to, BAK,organo-mercurials, such as thimerosal and phenylmercuric acetate andnitrate, quaternary ammonium compounds, methyl and propyl parabens,benzl alcohol, phenylethanol and the like. Because of the fungistaticactivity of the quinolone components of the present compositions, theconcentration of the preservative component, if present at all, in thepresent compositions may be, and preferably is, reduced, more preferablyby at least about 10% or at least about 20%, relative to theconcentration of the preservative needed in a similar compositionincluding, in place of the presently useful quinolone component withfungistatic activity, an antibiotic component without such fungistaticactivity and still be effectively preserved, for example, adequatelypreserved to pass the applicable United States and/or Europeanpreservative efficacy tests.

[0045] The present compositions may include effective amounts ofchelating or sequestering components, such as ethylene diaminetetraacetic acid (EDTA), citric acid, tartaric acid and the like.

[0046] Other optional excipients useful in the present compositionsinclude stabilizing agents such as antioxidants, for example, alkalimetal metabisulfates, ascorbic acid and the like.

[0047] The carrier component may be in various forms. In one embodiment,the carrier component comprises a liquid, and the composition may be asolution or a suspension. In either situation, the carrier may simplycontain water and one or more auxiliary components noted elsewhereherein.

[0048] The present compositions may be in any suitable form effective tobe administered to the eye. Such forms include solutions, suspensions,ointments, gels, solids and the like. An ointment may be considered as aform intermediate between a suspension and a gel. Each of these forms ofthe present compositions can be prepared using techniques and processingwhich are conventional and well known in the art.

[0049] In another embodiment, the carrier component may be in the formof a clear material which forms a semi-solid “gel” at human bodytemperatures. Various polymers, many of which are conventional and wellknown in the art, can be included in the carrier components to providethe present compositions in the form of gels. For example, a polymersystem including alkylene diamine tetra substituted with about 40% toabout 80% poly(oxyethylene) units and about 20% to about 60%poly(oxypropylene) units may be employed. The molecular weight of thepolymer used preferably is at least about 7,000 and can be as high asabout 50,000, more preferably in the range of about 7,000 to about30,000. The gel forming component, if any is present in an amounteffective to provide the composition in the form of a gel. For example,such gel forming component may be present in an amount in a range ofabout 10% or less to about 50% or more by weight of the total carriercomponent.

[0050] The compositions may also be in the form of solid inserts, forexample a solid dosage form that is suitable for insertion into thecul-de-sac of a mammalian eye. To this end, the composition componentscan be included with a non-bioerodible insert, for example, one whichafter dispensing the active component or components remains essentiallyintact, or a bio-erodible insert, for example, one that either issoluble in lacrimal fluids, or otherwise disintegrates.

[0051] A solid water soluble polymer may be employed in the carriercomponent. Such polymers include, for example, cellulose derivativessuch as methylcellulose, sodium carboxymethyl cellulose, or a hydroxylower alkyl cellulose such as hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose and the like; acrylates such aspolyacrylic acid salts, ethyl acrylates, polyacrylamides, naturalproducts such as gelatin, alginates, pectins, tragacanth, daraya,chondrus, agar, acacia; the starch derivatives such as starch acetate,hydroxyethyl starch ethers, hydroxypropy starch, as well as othersynthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone,polyvinyl methyl ether, polyethylene oxide, neutralized carbopol andxanthan gum, mixtures thereof and the like.

[0052] The present compositions may be prepared using conventionaltechniques, for example, by formation of solutions, gels, suspensions,etc., using well known and conventional techniques. For a more detaileddiscussion of the preparation and administration of ophthalmicformulations see Remingtons Pharmaceutical Sciences, 15 Ed., Pgs. 1489to 1504 (1975) which is incorporated in its entirety herein byreference.

[0053] In general, the present methods for treating mammalian eyescomprise administering to the mammalian eye a therapeutically effectiveamount of the present composition thereby providing an effectiveantibiotic in the mammalian eye and reducing inflammation and/or pain inthe mammalian eye.

[0054] Methods for treating corneal injuries, such as corneal ulcers,are also included within the scope of the present invention. Suchmethods comprise administering to a mammalian, preferably human, eyehaving a corneal injury a therapeutically effective amount of acomposition comprising a quinolone component in an amount effective asan antibiotic in the mammalian eye and a NSAID component in an amounteffective, in combination with the quinolone component, to provide areduction in pain caused by the corneal injury. Such reduction in pain,together with the antibiotic effectiveness of the presently usefulcompositions reduces the discomfort to the patient resulting from thecorneal injury and facilitates or promotes the healing of the injury.Corneal injuries include, but are not limited to, abrasions,lacerations, scratches, surgical trauma, accidental or incidentaltrauma, bruises and the like to the cornea which are infected or arelikely to become infected which cause pain to the mammal.

[0055] The present useful corneal injury-treating compositionspreferably include a carrier component in an amount effective to act asa carrier for the quinolone component and the NSAID component in thepresently useful compositions.

[0056] The quinolone components, NSAID components and carrier componentsuseful in treating corneal injuries preferably are as describedelsewhere herein. The presently useful compositions can be in anysuitable form effective to treat the corneal injury, preferably in aform as described elsewhere herein.

[0057] Methods for treating ocular infections, such as cornealinfections, are also included within the scope of the present invention.Such infections are caused by the presence of one or more microbes orpathogens in or on the eye in an amount or quantity to detrimentallyaffect the eye, for example, causing irritation, inflammation, redness,pain, tissue damage and the like. Examples of such infections include,but are not limited to, keratitis, such as bacterial keratitis, as wellas bacterial conjunctivitis and the like infections. The presentinfection treating methods comprise administering to a mammalian,preferably human, eye having an infection caused by one or more microbesor pathogens a therapeutically effective amount of a compositioncomprising a quinolone component in an amount effective as an antibioticin the mammalian eye and an effective amount of a NSAID component.

[0058] In one embodiment, the NSAID component is effective to reduce thetime needed to eliminate the infection relative to identicallyadministering a similar composition without the NSAID component. Inaddition, or alternately, the administering step, and preferably theNSAID component used in the administering step, is effective to at leastinhibit the one or more microbes or pathogens causing the infection fromadhering to a surface of the eye. In a very useful embodiment, theadministering step, and preferably the NSAID component used in theadministering step, is effective to at least inhibit, or evensubstantially prevent, colonization of the one or more microbes orpathogens in the eye.

[0059] The presently useful ocular infection-treating compositionspreferably include a carrier component in an amount effective to act asa carrier for the quinolone component and the NSAID component in thepresently useful compositions.

[0060] The quinolone components, NSAID components and carrier componentsuseful in treating ocular infections preferably are as describedelsewhere herein. The presently useful compositions can be in anysuitable form effective to treat the ocular infection, preferably in aform as described elsewhere herein.

[0061] The present use methods may be considered to be curative and/orpreventative when applied, presurgically or immediately posttraumatically, that is before a microbial infection develops, or beforeinflammation and/or pain and/or infection is apparent. The present usemethods are effective to reduce the risk of the formation of suchinfections and to reduce the severity of any inflammation or pain whichmay develop.

[0062] The present methods of use, including the general methods of use,the methods of treating corneal ulcers and the methods of treatingocular infections, may involve any suitable administration step or stepsto provide an effective amount of the composition to the mammalian eye.Such administering may include, but is not limited to, topicalapplication to the eye, instillation into the eye, placing an insertinto the cul-de-sac (space) between the eyeball and the eyelid and thelike. Other conventional methods of administering compositions to theeye may be employed provided that the compositions are administered soas to provide the benefits desired.

[0063] The dosage level of the composition depends, of course, on manyfactors, for example, the particular application involved, theparticular active components employed, the concentration of the activecomponents in the composition, the severity of theinfection/inflammation/pain/corneal ulcer and the individual's responseto the treatment. Such dosage can be easily determined by routine andwell known techniques to achieve the desired results in the individualpatient being treated.

[0064] The following non-limiting examples illustrate certain aspects ofthe present invention.

EXAMPLES 1 TO 11

[0065] A series of compositions, Compositions 1 to 11, are prepared byblending various components together. These compositions have thefollowing chemical make-ups. Composition 1 Ofloxacin 0.6 w/v % NaCl 0.79w/v % pH 6.4 water q.s. 100% Composition 2 Ofloxacin 1.0 w/v % NaCl 0.79w/v % pH 6.4 water q.s. 100% Composition 3 Ofloxacin 0.6 w/v % NaCl 0.3w/v % EDTA 0.1 wt % Boric Acid 1.0 w/v % pH 6.4 water q.s. 100%Composition 4 Ofloxacin 1.0 w/v % NaCl 0.3 w/v % EDTA 0.1 w/v % BoricAcid 1.0 w/v % pH 6.4 water q.s. 100% Composition 5 Ketorolac 0.5 w/v %Ofloxacin 0.6 w/v % NaCl 0.79 w/v % pH 6.4 water q.s. 100% Composition 6Ketorolac 0.5 w/v % Ofloxacin 1.0 w/v % NaCl 0.79 w/v % pH 6.4 waterq.s. 100% Composition 7 Ketorolac 0.5 w/v % Ofloxacin 0.6 w/v % NaCl 0.3w/v % EDTA 0.1 w/v % Boric Acid 1.0 w/v % pH 6.4 water q.s. 100%Composition 8 Ketorolac 0.5 w/v % Ofloxacin 1.0 w/v % NaCl 0.3 w/v %EDTA 0.1 w/v % Boric Acid 1.0 w/v % pH 6.4 water q.s. 100% Composition 9Ketorolac 0.5 w/v % Ofloxacin 0.3 w/v % NaCl 0.79 w/v % BAK 0.005 w/v %L-Arginine 0.28 w/v % pH 6.4 water q.s. 100% Composition 10 Ketorolac0.5 w/v % Ofloxacin 0.3 w/v % NaCl 0.79 w/v % BAK 0.005 w/v % METHOCEL ®⁽¹⁾ 0.1 w/v % Carbopol ⁽²⁾ 0.2 w/v % pH 6.4 water q.s. 100% Composition11 Ofloxacin 0.3 w/v % BAK 0.005 w/v % METHOCEL ® ⁽¹⁾ 0.1 w/v % Carbopol⁽²⁾ 0.225 w/v % Glycerine 2.6 w/v % pH 6.5 water q.s. 100%

[0066] An abbreviated preservative efficacy test of each of thesecompositions is performed using S. aureus ATCC 6538 and A. niger ATCC16404 as the test organisms. The compositions are tested against PhEur-A/B and USP criteria according to ARM T-005. Ten (10) milliliter ofeach composition is challenged with approximately 10⁵ cfu/ml of testorganism. At the appropriate time intervals, the amount of bacterial andfungal survivors are assayed using Dey Engley broth (DE) as theneutralizer media. DE, along with filtration, is sufficient atneutralizing the antimicrobial agents in the compositions. One (1) ml ofeach sample is diluted into nine (9) ml of DE. One (1) of the 1:10dilution is filtered through a 0.45 μm filter and washed with 100 mlsaline/TWEEN® 80. After washing the filter a second time with 100 ml ofa saline/TWEEN® 80 solution, the filtrate is placed onto a TSA plate forbacteria and SAB for fungi. The same procedure as stated above wasfollowed for composition 11 (which is in the form of a gel) except a1:100 dilution of the product is made prior to filtration (0.1 ml ofproduct is added to 10 ml DE).

[0067] A summary of the results of these preservative efficacy tests isas follows: Composition USP Ph Eur-A Ph Eur-B 1 PASS FAIL Marginal PASS2 PASS FAIL FAIL 3 PASS FAIL Marginal PASS 4 PASS FAIL PASS 5 PASS FAILFAIL 6 PASS FAIL FAIL 7 PASS PASS Marginal PASS 8 PASS FAIL PASS 9 PASSPASS PASS 10 PASS PASS PASS 11 PASS PASS PASS

[0068] Detailed results of the preservative efficacy tests were asfollows: Test Organism Inoculum Test Compositions level Interval 1 2 3 45 6 S. aureus 6 hours 2 × 10⁵ 9 × 10⁴ 1 × 10⁵ 8 × 10⁴ 8 × 10⁴ 1 × 10⁵ATTC 6538 24 hours 7 × 10⁴ 3 × 10⁴ 6 × 10⁴ <10 8 × 10³ 2 × 10³ 4 × 10⁵ 7days <10 <10 <10 1 × 10¹ <10 <10 14 days <10 <10 <10 <10 <10 <10 28 days<10 <10 <10 <10 <10 <10 A. niger 7 days 8 × 10⁴ 8 × 10⁴ 4 × 10³ 1 × 10³7 × 10⁴ 7 × 10⁴ ATCC 16404 14 days 2 × 10⁴ 3 × 10⁴ 2 × 10³ 1 × 10³ 9 ×10⁴ 9 × 10⁴ 1 × 10⁵ 28 days 1 × 10⁴ 3 × 10⁴ 2 × 10³ 8 × 10² 2 × 10⁴ 1 ×10⁴ Test Organism Inoculum Compositions level Test Interval 7 8 9 10 11S. aureus 6 hours 1 × 10⁵ 1 × 10⁵ <10 <10 <10 ATTC 6538 24 hours 3 × 10³1 × 10⁴ <10 <10 <10 4 × 10⁵ 7 days <10 <10 <10 <10 <10 14 days <10 <10<10 <10 <10 28 days <10 <10 <10 <10 <10 A. niger 7 days 2 × 10⁴ 3 × 10³1 × 10¹ <10 1 × 10¹ ATCC 16404 14 days 2 × 10⁴ 7 × 10³ <10 <10 <10 1 ×10⁵ 28 days 4 × 10² 1 × 10² <10 <10  <1 

[0069] All of the compositions very effectively pass the USPET. Inparticular, the fact that Compositions 1 to 8, which include nocomponent known to be effective as a preservative, pass the USPET issurprising, especially since prior art compositions which have includeda quinolone, such as ofloxacin, have included preservatives, such asBAK. In addition, Compositions 1 to 8 have sufficient antifungalactivity to prevent A. niger from increasing in population. Thus, thequinolone, ofloxacin, included in these compositions has sufficientfungistatic activity to act as a preservative for the compositionagainst A. niger contamination.

EXAMPLES 12 TO 23

[0070] A further series of compositions, Compositions 12 to 24, areprepared by blending various components together. These compositionshave the following chemical make-ups. Each composition includedsufficient water to total 100% by weight. EXAMPLE NO. ACTIVESCONCENTRATION, w/v % 12 Ketorolac 0.5 Ofloxacin 0.3 NaCl 0.79 pH 6.4 13Ketorolac 0.5 Ofloxacin 0.3 NaCl 0.30 EDTA 0.1 Boric Acid 1.0 pH 6.4 14Ketorolac 0.5 Ofloxacin 0.3 NaCl 0.79 BAK 0.005 pH 6.4 15 Ketorolac 0.5Ofloxacin 0.3 NaCl 0.79 pH 7.4 16 Ketorolac 0.5 Ofloxacin 0.3 NaCl 0.79BAK 0.005 pH 7.6 17 Ketorolac 0.5 Ofloxacin 0.3 NaCl 0.79 BAK 0.005Octoxynol ⁽³⁾ 0.007 pH 6.4 18 Ketorolac 0.5 Ofloxacin 0.3 NaCl 0.79 BAK0.005 Octoxynol ⁽³⁾ 0.007 pH 7.6 19 Ketorolac 0.5 Ofloxacin 0.3 NaCl0.79 BAK 0.005 Cyclodextrin⁽⁴⁾ 0.1 pH 6.4 20 Ketorolac 0.5 Ofloxacin 0.5NaCl 0.79 BAK 0.005 Cyclodextrin⁽⁴⁾ 0.1 pH 7.6 21 Ketorolac 0.5Ofloxacin 0.3 NaCl 0.79 Purite ⁽⁵⁾ 0.007 pH 7.6 22 Ketorolac 0.5Ofloxacin 0.3 NaCl 0.79 Purite ⁽⁵⁾ 0.007 Octoxynol⁽³⁾ 0.007 pH 7.6 23Ketorolac 0.5 Ofloxacin 0.3 NaCl 0.79 Purite ⁽⁵⁾ 0.007 Cyclodextrin⁽⁴⁾0.1 pH 7.6

[0071] The samples were tested for preservative efficacy against PhEur-A/B and USP criteria according to ARM T-005. Ten (10) milliliters ofeach sample was challenged with approximately 10⁵ cfu/ml of testorganism. The test organisms included S. aureus ATCC 6538, P. aeruginosaATCC 9027, E. coli ATCC 8739, C. albicans ATCC 10231, and A. niger ATCC16404. At the appropriate time intervals, the amount of bacterial andfungal survivors were assayed using DE as the neutralizer media. DE,along with filtration, is sufficient at neutralizing the antimicrobialagents in the compositions. One (1) ml of each sample was diluted into 9ml of DE. The whole 10 ml was filtered through a 0.45 um filter andwashed with 100 ml of phosphate buffered saline pH 5.4. After washingthe filter a second time with 100 ml phosphate buffered saline/TWEEN®80, the filter was placed onto a blood agar plate for bacteria and SABfor fungi.

[0072] The results are summarized in the below table. SAMPLE ID USP PhEur-A Ph Eur-B 12 PASS FAIL FAIL 13 PASS FAIL FAIL 14 PASS PASS PASS 15PASS FAIL FAIL 16 PASS PASS PASS 17 PASS PASS PASS 18 PASS PASS PASS 19PASS FAIL PASS 20 PASS PASS PASS 21 PASS FAIL FAIL 22 PASS FAIL FAIL 23PASS FAIL FAIL

[0073] Detailed results of the preservation efficacy tests onCompositions 12 to 17 were as follows: Test Organism CompositionInoculum level Test Interval 12 13 14 15 16 17 S. aureus 6 hours 2 × 10⁵2 × 10⁵ 4 3 × 10⁵ <10 1 ATTC 6538 24 hours 2 × 10⁵ 2 × 10⁵ <10 3 × 10⁵<10 <10 5 × 10⁵ 7 days <10 2 × 10¹ <10 <10 <10 <10 14 days <10 <10 <10<10 <10 <10 28 days <10 <10 <10 <10 <10 <10 P. aeruginosa 6 hours <10<10 <10 <10 <10 <10 ATCC 9027 24 hours <10 <10 <10 <10 <10 <10 3 × 10⁵ 7days <10 2 × 10¹ <10 <10 <10 <10 14 days <10 <10 <10 <10 <10 <10 28 days<10 <10 <10 <10 <10 <10 E. coli 6 hours 6 × 10¹ 5 × 10¹ <10 5 × 10¹ <10<10 ATCC 8739 24 hours 5 × 10² <10 <10 <10 <10 <10 5 × 10⁵ 7 days <10<10 <10 <10 <10 <10 14 days <10 <10 <10 <10 <10 <10 28 days <10 <10 <10<10 <10 <10 C. albicans 7 days 1 × 10⁵ 2 × 10⁵ <10 3 × 10⁵ <10 <10 ATCC10231 14 days 1 × 10⁵ 2 × 10⁵ <10 1 × 10⁵ <10 <10 3 × 10⁵ 28 days 8 ×10⁴ 9 × 10⁴ <10 9 × 10⁴ <10 <10 A. niger 7 days 6 × 10⁴ 6 × 10⁴ 3 × 10¹7 × 10⁴ <10 3 × 10¹ ATCC 16404 14 days 4 × 10⁴ 3 × 10⁴  4 6 × 10⁴ 1 ×10² <10 1 × 10⁵ 28 days 3 × 10⁴ 3 × 10⁴ <10 4 × 10⁴ <10 <10

[0074] All of the Compositions pass the USPET. Compositions 12 15,include no component known to be effective as a preservative. AlthoughCompositions 12 and 15 do not pass the European Preservative EfficacyTests, they do have sufficient antifungal activity to prevent C.albicans and A. niger from increasing in population. The quinolone,ofloxacin, included in these compositions has sufficient fungistaticactivity to act as a preservative for the composition against C.albicans and A. niger contamination.

EXAMPLES 24 TO 41

[0075] Compositions 5 to 10 and 12 to 23 are each administered to ahuman eye which has been subjected to surgical trauma. Beforeadministration, each eye exhibits a degree of inflammation and is thesource of a degree of pain.

[0076] Each composition which is a solution is administered to the eyein an amount of about 1 to 2 drops per eye with the drops containingabout 25 to 50 micro liters. The drops are administered 3 to 4 times perday. Each composition which is a gel is administered by placing about 50to 100 micro liters of the composition between the eye lid and the eyeball 3 to 4 times a day.

[0077] After a week of such administering, each of the eyes treatedexhibits no inflammation and is not a source of pain. In addition, eachof the eyes has remained free of microbial infection.

EXAMPLES 42 TO 59

[0078] Compositions 5 to 10 and 12 to 23 are each administered to ahuman eye which has a corneal ulcer. Before administration, each eye isthe source of a substantial degree of pain.

[0079] Each composition which is a solution is administered to the eyein an amount of about 1 to 2 drops per eye with the drops containingabout 25 to 50 micro liters. The drops are administered every 30minutes. Each composition which is a gel is administered by placingabout 50 to 100 micro liters. of the composition between the eye lid andthe eye ball every 30 minutes.

[0080] Within one day after the initial administering, the painresulting from each of the corneal ulcers is substantially eliminated.After two weeks of such administering, each of the corneal ulcers hassubstantially completely healed and no pain from the ulcer isexperienced. In addition, each of the eyes has remained free ofmicrobial infection.

EXAMPLES 60 TO 78

[0081] Compositions 5 to 10 and 12 to 23 are each administered to ahuman eye which has a corneal microbial infection.

[0082] Each composition which is a solution is administered to the eyein an amount of about 1 to 2 drops per eye with the drops containingabout 25 to 50 micro liters. The drops are administered every 30minutes. Each composition which is a gel is administered by placingabout 50 to 100 micro liters of the composition between the eye lid andthe eye ball every 30 minutes.

[0083] After a period of time, on the order of from about 4 days toabout 14 days, of such administering, each of the corneal microbialinfections has been substantially completely eliminated and no pain fromthe infection is experienced. Using such compositions to treat theseocular infections, a reduced time period of administering thecompositions is needed to substantially completely eliminate theinfection relative to similar compositions without the NSAID component,ketorolac. The NSAID component is believed to inhibit the colonizationof the microbes or pathogens causing the ocular infections. For example,the NSAID component in the composition administered may inhibit orsubstantially prevent the offending microbes or pathogens from adheringto one or more surfaces of the eye, thereby inhibiting the spread orprogress of the infection. The infection is resolved or eliminated morequickly using the present quinolone, NSAID-containing compositionsrelative to using similar compositions without the NSAID component.

[0084] While this invention has been described with respect to variousspecific examples and embodiments, it is to be understood that theinvention is not limited thereto and that it can be variously practicedwithin the scope of the following claims.

What is claimed is:
 1. A composition comprising: a quinolone componentin an amount effective as an antibiotic when the composition is placedin a mammalian eye, the quinolone component in the compositions havingfungistatic activity; a NSAID component in an amount effective to reduceinflammation or pain when the composition is placed in a mammalian eye;and a carrier component in an amount effective to act as a carrier forthe quinolone component and the NSAID component in the composition, thecarrier component being ophthalmically acceptable.
 2. The composition ofclaim 1 wherein the NSAID component is a ketorolac component.
 3. Thecomposition of claim 1 or 2 wherein the quinolone component is anofloxacin component.
 4. The composition of any of claims 1-3 whereinsaid composition contains substantially no addition components which areactive as a preservative.
 5. A method for treating a mammalian eyecomprising: administering to the mammalian eye a therapeuticallyeffective amount of the composition of any of claims 1-4, therebyproviding an effective antibiotic in the mammalian eye and reducinginflammation or pain in the mammalian eye.
 6. A method for reducing painin a mammalian eye comprising: administering to a mammalian eye in needof pain reduction a therapeutically effective amount of the compositionof claims 1-4 in an amount effective to provide a reduction in pain tothe mammalian eye.
 7. A method for treating a corneal injury comprising:administering to a mammalian eye having a corneal injury atherapeutically effective amount of a composition comprising a quinolonecomponent in an amount effective as an antibiotic in the mammalian eyeand a NSAID component in an amount effective, in combination with thequinolone component, to provide a reduction in paid caused by thecorneal injury.
 8. The method of claim 9 wherein the quinolone componentis an ofloxacin component, the NSAID component is a ketorolac component,and the corneal injury is a corneal ulcer.
 9. A method for treating anocular infection comprising: administering to a mammalian eye having aninfection caused by one or more pathogens a therapeutically effectiveamount of a composition comprising a quinolone component in an amounteffective as an antibiotic in the mammalian eye and a NSAID component inan amount effective to reduce the time needed to eliminate the infectionrelative to identically administering a similar composition without theNSAID component.
 10. The method of claim 9 wherein the administeringstep is effective to inhibit colonization of the one or more pathogensin the mammalian eye.
 11. The method of claim 9 or 10 wherein themammalian eye includes a surface and the administering step is effectiveto at least inhibit the one or more pathogens from adhering to thesurface.
 12. The method of any of claims 9-11 wherein the ocularinfection is a corneal infection.
 13. The method of any of claims 9-12wherein the administering step is effective to inhibit colonization ofthe one or more pathogens in the mammalian eye.
 14. The method of any ofclaims 9-13 wherein the administering step is effective to at leastinhibit the one or more pathogens from adhering to a cornea of the eye.15. The method of any of claims 9-14 herein the quinolone component is ahalogenated quinolone component.
 16. The method of claim 15 wherein thequinolone component is a fluorinated quinolone component.
 17. The methodof claim 16 wherein the quinolone component is an ofloxacin component.18. The method of any of claims 9-17 wherein said composition containssubstantially no additional components which are active aspreservatives.
 19. The method of any of claims 9-18 wherein the NSAIDcomponent is a carboxyl group-containing NSAID component.
 20. The methodof claim 19 wherein the NSAID component is a ketorolac component.
 21. Amethod for treating an ocular infection comprising: administering to amammalian including at least one surface; and an eye having an infectioncaused by one or more pathogens a therapeutically effective amount of acomposition comprising a quinolone component in an amount effective asan antibiotic in the mammalian eye and an NSAID component in an amounteffective to at least inhibit the one or more pathogens from adhering tothe surface.
 22. A method for treating an ocular infection comprising:administering to a mammalian eye having an infection caused by one ormore pathogens a therapeutically effective amount of a compositioncomprising a quinolone component in an amount effective as an antibioticin the mammalian eye and a NSAID component in an amount effective toinhibit colonization of the one or more pathogens in the mammalian eye.23. The method of either of claims 21 or 22 wherein the ocular infectionis a corneal infection.
 24. The method of any of claims 21-23 whereinthe quinolone component is a halogenated quinolone component.
 25. Themethod of any of claims 21-24 wherein the quinolone component is afluorinated quinolone component.
 26. The method of any of claims 21-25wherein the quinolone component is an ofloxacin component.
 27. Themethod of claim 26 wherein the quinolone component is an ofloxacincomponent
 28. The method of any of claims 21-27 wherein the NSAIDcomponent is a carboxyl group-containing NSAID component.
 29. The methodof any of claims 21-28 wherein the NSAID component is a ketorolaccomponent.
 30. A composition comprising: a quinolone component in anamount effective as an antibiotic when the composition is placed in amammalian eye, the quinolone component in the compositions havingfungistatic activity; a carrier component in an amount effective to actas a carrier for the quinolone component and the NSAID component in thecomposition, the carrier component being ophthalmically acceptable;wherein said composition contains substantially no additional componentseffective to act as a preservative.
 31. The composition of claims 30wherein said quinolone component is a fluorinated quinolone component.32. The composition of claim 31 wherein said quinolone component isolfloxacin.